Biological Signatures of Alzheimer’s Disease

2020 ◽  
Vol 20 (9) ◽  
pp. 770-781 ◽  
Author(s):  
Poornima Sharma ◽  
Anjali Sharma ◽  
Faizana Fayaz ◽  
Sharad Wakode ◽  
Faheem H. Pottoo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Senile Plaque ◽  
Senile Plaques ◽  
Amyloid Deposition ◽  
Immune Defense ◽  
Amyloid Angiopathy ◽  
Microvascular Changes ◽  
Β Amyloid

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

scholarly journals β-Amyloid Degradation and Alzheimer's Disease

2006 ◽  
Vol 2006 ◽  
pp. 1-12 ◽  
Author(s):  
Deng-Shun Wang ◽  
Dennis W. Dickson ◽  
James S. Malter
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Current Knowledge ◽  
Senile Plaques ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Converting Enzyme ◽  
Insulin Degrading Enzyme ◽  
Amyloid A ◽  
Β Amyloid

Extensiveβ-amyloid (Aβ) deposits in brain parenchyma in the form of senile plaques and in blood vessels in the form of amyloid angiopathy are pathological hallmarks of Alzheimer's disease (AD). The mechanisms underlying Aβdeposition remain unclear. Major efforts have focused on Aβproduction, but there is little to suggest that increased production of Aβplays a role in Aβdeposition, except for rare familial forms of AD. Thus, other mechanisms must be involved in the accumulation of Aβin AD. Recent data shows that impaired clearance may play an important role in Aβaccumulation in the pathogenesis of AD. This review focuses on our current knowledge of Aβ-degrading enzymes, including neprilysin (NEP), endothelin-converting enzyme (ECE), insulin-degrading enzyme (IDE), angiotensin-converting enzyme (ACE), and the plasmin/uPA/tPA system as they relate to amyloid deposition in AD.

Aß Monomer, Oligomer and Fibril in Alzheimer's Disease

2011 ◽  
pp. 125-131
Author(s):  
Hiroshi Mori
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Angiopathy ◽  
Gamma Secretase ◽  
Aged People ◽  
Theoretical Predictions ◽  
Prevalent Disease

Alzheimer’s disease (AD), the most prevalent disease of aged people, is a progressive neurodegenerative disorder with dementia. Amyloid-ß (also known as ß-protein and referred to here as Aß) is a well-established, seminal peptide in AD that is produced from the amyloid precursor protein (APP) by consecutive digestion with the ß secretase of BACE (beta-site amyloid cleaving enzyme) and gamma secretase of the presenilin complex. Abnormal cerebral accumulation of Abeta in the form of insoluble fibrils in senile plaques and cerebral amyloid angiopathy (CAA) is a neuropathological hallmark of AD. In contrast to insoluble fibrillary Aß, a soluble oligomeric complex, ADDL, consists of low-n oligomers of Aß, such as Aß*56. Despite their different names, it is currently proposed that oligomeric Aß is directly involved in synaptic toxicity and cognitive dysfunction in the early stages of AD. This chapter identifies a novel APP mutation (E693delta; referred to as the Osaka mutation) in a pedigree with probable AD, resulting in a variant Aß lacking glutamate at position 22. Based on theoretical predictions and in vitro studies on synthetic mutant Aß peptides, the mutated Aß peptide showed a unique and enhanced oligomerization activity without fibrillization. This was further confirmed by PiB-PET analysis on the proband patient. Collectively, the chapter concludes that the Osaka mutation is the first human evidence for the hypothesis that oligomeric Aß is involved in AD.

FINANCIAL MANAGEMENT SKILLS IN AGING, MCI AND DEMENTIA: CROSS SECTIONAL RELATIONSHIP TO 18F-FLORBETAPIR PET CORTICAL Β-AMYLOID DEPOSITION

2019 ◽  
pp. 1-9
Author(s):  
S. Tolbert ◽  
Y. Liu ◽  
C. Hellegers ◽  
J.R. Petrella ◽  
M.W. Weiner ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
At Risk ◽  
Amyloid Deposition ◽  
Cross Sectional ◽  
Cognitively Normal ◽  
Financial Capacity ◽  
Cohen’S D ◽  
Β Amyloid ◽  
Cohen's D

Background: There is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer’s disease (AD) and their pathological substrates. Objectives: To test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD. Design: Cross-sectional analyses of data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada. Setting: Multicenter biomarker study. Participants: 243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD). Measurements: 18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual’s financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0–74) with higher scores indicating better financial skill. Results: FCI-SF total score was significantly worse in MCI [Cohen’s d= 0.9 (95%CI: 0.6-1.2)] and AD subjects [Cohen’s d=3.1(CI: 2.5-3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen’s f2=0.751(CI: 0.5-1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen’s f2=0.198(CI: 0.06-0.37)]. Conclusion: Using a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.

scholarly journals CSF β-amyloid and white matter damage: a new perspective on Alzheimer’s disease

2017 ◽  
Vol 89 (4) ◽  
pp. 352-357 ◽  
Author(s):  
Anna M Pietroboni ◽  
Marta Scarioni ◽  
Tiziana Carandini ◽  
Paola Basilico ◽  
Marcello Cadioli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Statistical Tests ◽  
Brain Mri ◽  
Healthy Controls ◽  
Microstructural Damage ◽  
Amyloid Pathology ◽  
Apparent Diffusion Coefficient Value ◽  
Β Amyloid

ObjectiveTo assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls.MethodsEighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aβ levels (Aβ(+)), while 23 had normal CSF Aβ levels (Aβ(−)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.ResultsWe found an increased WM-LL in Aβ(+) compared with both, healthy controls (p=0.003) and Aβ(−) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor of patients’ WM-LL (r=−0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001).ConclusionsWM damage is crucial in AD pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.

scholarly journals White matter hyperintensities: relationship to amyloid and tau burden

Brain ◽  
2019 ◽  
Vol 142 (8) ◽  
pp. 2483-2491 ◽  
Author(s):  
Jonathan Graff-Radford ◽  
Eider M Arenaza-Urquijo ◽  
David S Knopman ◽  
Christopher G Schwarz ◽  
Robert D Brown ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Cerebral Microbleeds ◽  
Amyloid Angiopathy ◽  
Amyloid Pet ◽  
Gradient Recall Echo ◽  
Tau Pet ◽  
Topographic Pattern

Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

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